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The management of diabetic retinopathy (DR) has evolved considerably over the past decade, with the availability of new technologies (diagnostic and therapeutic). As such, the existing Royal College of Ophthalmologists DR Guidelines (2013) are outdated, and to the best of our knowledge are not under revision at present. Furthermore, there are no other UK guidelines covering all available treatments, and there seems to be significant variation around the UK in the management of diabetic macular oedema (DMO). This manuscript provides a summary of reviews the pathogenesis of DR and DMO, including role of vascular endothelial growth factor (VEGF) and non-VEGF cytokines, clinical grading/classification of DMO vis a vis current terminology (of centre-involving [CI-DMO], or non-centre involving [nCI-DMO], systemic risks and their management). The excellent UK DR Screening (DRS) service has continued to evolve and remains world-leading. However, challenges remain, as there are significant variations in equipment used, and reproducible standards of DMO screening nationally. The interphase between DRS and the hospital eye service can only be strengthened with further improvements. The role of modern technology including optical coherence tomography (OCT) and wide-field imaging, and working practices including virtual clinics and their potential in increasing clinic capacity and improving patient experiences and outcomes are discussed. Similarly, potential roles of home monitoring in diabetic eyes in the future are explored. The role of pharmacological (intravitreal injections [IVT] of anti-VEGFs and steroids) and laser therapies are summarised. Generally, IVT anti-VEGF are offered as first line pharmacologic therapy. As requirements of diabetic patients in particular patient groups may vary, including pregnant women, children, and persons with learning difficulties, it is important that DR management is personalised in such particular patient groups. First choice therapy needs to be individualised in these cases and may be intravitreal steroids rather than the standard choice of anti-VEGF agents. Some of these, but not all, are discussed in this document.

SARS-CoV-2 induces a muted innate immune response compared to other respiratory viruses. Mitochondrial dynamics might partially mediate this effect of SARS-CoV-2 on innate immunity. Polypeptides encoded by open reading frames of SARS-CoV and SARS-CoV-2 have been shown to localize to mitochondria and disrupt Mitochondrial Antiviral Signaling (MAVS) protein signaling. Therefore, we hypothesized that SARS-CoV-2 would distinctly regulate the mitochondrial transcriptome. We analyzed multiple publicly available RNASeq data derived from primary cells, cell lines, and clinical samples (i.e., BALF and lung). We report that SARS-CoV-2 did not dramatically regulate (1) mtDNA-encoded gene expression or (2) MAVS expression, and (3) SARS-CoV-2 downregulated nuclear-encoded mitochondrial (NEM) genes related to cellular respiration and Complex I.

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer’s disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry—the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer’s disease, and microproteins.

ObjectivesThis report aims to provide clear recommendations and practical guidance from a panel of UK retinal experts on an aflibercept treat-and-extend (T&E) pathway that can be implemented in clinical practice. These recommendations may help service providers across the NHS intending to implement a T&E approach, with the aim of effectively addressing the capacity and resource issues putting strain on UK neovascular age-related macular degeneration (nAMD) services while promoting patients’ best interests throughout.MethodsTwo structured roundtable meetings of retinal specialists were held in London, UK on 7 December 2018 and 1 March 2019. These meetings were organised and funded by Bayer.ResultsThe panel provided recommendations for an aflibercept T&E pathway and developed specific criteria based on visual acuity, retinal morphology and optical coherence tomography imaging to guide reduction, maintenance and extension of injection intervals. They also discussed the extension of treatment intervals by 2- or 4-week adjustments to a maximum treatment interval of 16 weeks, the management of retinal fluid and the stopping of treatment.ConclusionsThe long-term benefits of implementing a T&E pathway may include superior visual outcomes compared with a pro re nata (PRN; as needed) protocol, and a lower treatment burden compared with a fixed protocol, which is likely to improve service capacity. Furthermore, the predictable nature of a T&E approach compared with a PRN service may aid capacity planning for the future nAMD treatment demand.

This review assessed the real-world evidence of the management of macular oedema secondary to branch retinal vein occlusion (BRVO). A meta-analysis of 2530 eyes from 48 real-world studies of therapies for macular oedema secondary to BRVO was conducted. Baseline characteristics, visual, anatomical and safety outcomes were recorded. The weighted mean and weighted estimates from random-effects models were calculated for visual acuity (VA) and central subfield thickness (CST) changes at 6, 12 and 24 months. Primary outcome was change in VA (logMAR letters) at 12 months. Study quality was assessed using the quality appraisal checklist for case series developed by Institute of Health Economics. The mean baseline VA for the pooled data was 54.0 (51.5, 56.5) letters and the mean baseline CST was 501.3 (483.5, 519.1) µm. The random-effects estimate for mean (95% CI) change in VA was 14.6 (12.5, 16.7) letters at 12 months (n = 1727). The random-effects estimate for mean (95% CI) change in CST was −181.7 (−230.7, −132.7) µm at 12 months (n = 1325). The quality of studies varied considerably. Ocular and systemic adverse events were discussed in 79% and 42% of treatment arms respectively, with possible under-reporting. Visual and anatomical gains achieved in the real-world for anti-VEGF therapy were not as impressive as seminal RCTs, possibly due to reduced injection frequency in the real world and differences in baseline characteristics. There is an urgent need for consensus on the minimum efficacy, treatment burden and safety data to collect to strengthen the real-world evidence base.

IntroductionThe mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both humanin and small-humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism.ObjectivesBy using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects.MethodsPlasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS.ResultsHNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment.ConclusionsThe present study indicates that humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for humanin and SHLP2 treatment.

Mitochondrial genome-wide association studies identify mitochondrial single nucleotide polymorphisms (mtSNPs) that associate with disease or disease-related phenotypes. Most mitochondrial and nuclear genome-wide association studies adjust for genetic ancestry by including principal components derived from nuclear DNA, but not from mitochondrial DNA, as covariates in statistical regression analyses. Furthermore, there is no standard when controlling for genetic ancestry during mitochondrial and nuclear genetic interaction association scans, especially across ethnicities with substantial mitochondrial genetic heterogeneity. The purpose of this study is to (1) compare the degree of ethnic variation captured by principal components calculated from microarray-defined nuclear and mitochondrial DNA and (2) assess the utility of mitochondrial principal components for association studies. Analytic techniques used in this study include a principal component analysis for genetic ancestry, decision-tree classification for self-reported ethnicity, and linear regression for association tests. Data from the Health and Retirement Study, which includes self-reported White, Black, and Hispanic Americans, was used for all analyses. We report that (1) mitochondrial principal component analysis (PCA) captures ethnic variation to a similar or slightly greater degree than nuclear PCA in Blacks and Hispanics, (2) nuclear and mitochondrial DNA classify self-reported ethnicity to a high degree but with a similar level of error, and 3) mitochondrial principal components can be used as covariates to adjust for population stratification in association studies with complex traits, as demonstrated by our analysis of height—a phenotype with a high heritability. Overall, genetic association studies might reveal true and robust mtSNP associations when including mitochondrial principal components as regression covariates.

Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.

Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that humanin is an important factor in cognitive aging.

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers. A rare variant of the mitochondrial‐DNA‐encoded microprotein humanin interacts with APOE4 genotype in a small centenarian population. This humanin variant induces an amino acid change at its third residue from proline to serine (P3S). Humanin P3S binds to APOE4 and, upon administration to APP/PS1/APOE4 TR model mice, reduces amyloidosis.